The contribution by monoamine oxidase and catechol-O-methyltransferase to the total-body and pulmonary plasma clearance of catecholamines

Abstract

To study the effects of inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) on the removal of circulating catecholamines, anaesthetized rabbits were infused for 120 min with 3H-labelled noradrenaline, adrenaline and dopamine. Total-body plasma clearances (Cltot) and pulmonary fractional extractions (ERp) of the infused amines and the cardiac output of plasma (CO(p)) were determined under steady-state conditions at the end of each of two consecutive 60-min treatment periods. MAO and COMT were inhibited by treatment with pargyline (40 mg/kg) and tolcapone (3 mg/kg followed by 1.5 mg/kg given every 30 min), respectively. Two groups of animals were studied. Group I involved animals treated with tolcapone throughout and given pargyline at the beginning of the second treatment period. In group II, pargyline was given at the beginning of the first, and the treatment with tolcapone was started at the beginning of the second treatment period. As previous experiments had shown that COMT inhibition alone is without any effect on Cltot of the three catecholamines considered here, the results obtained in the first treatment period of group I can be taken to reflect control results. At the end of the first treatment period, Cltot of noradrenaline, adrenaline and dopamine (expressed as a percentage of CO(p)) was 88%, 85% and 142%, respectively, in group I (COMT inhibition) and 67%, 77% and 115%, respectively, in group II (MAO inhibition; P < 0.05 for the group difference regarding Cltot of noradrenaline and dopamine). MAO inhibition on top of COMT inhibition (group I) lowered Cltot of noradrenaline, adrenaline and dopamine by 23%, 12% and 26%, respectively, and COMT inhibition on top of MAO inhibition (group II) reduced Cltot of these catecholamines by 13%, 20% and 17%, respectively. At the end of the first treatment period, the pulmonary plasma clearance (Clp = ERp x CO(p)) of noradrenaline and dopamine was 13 and 25 ml kg-1 min-1, respectively, in group I and 12 and 28 ml kg-1 min-1, respectively, in group II. Clp of adrenaline did not differ from zero in either group. Clp of noradrenaline and dopamine was reduced by 74% and 70%, respectively, when both enzymes were inhibited in group I and by 70% and 67%, respectively, when both enzymes were inhibited in group II. Hence, inhibition of either MAO or COMT alone had little, if any, effect on the removal of noradrenaline, adrenaline and dopamine on passage through the systemic and pulmonary circulation. Combined inhibition of both MAO and COMT was highly effective in reducing the pulmonary clearance of noradrenaline and dopamine, but produced only minor decreases in the total-body clearance of all three catecholamines.

1,1′-Diisopropyl-2,4′-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines

“…The present results cannot be used to estimate total plasma clearances of the three catecholamines, because catecholamine clearances from arterial plasma do not reflect total-body plasma clearances (Friedgen et al 1994). However, for similar experimental conditions, Friedgen et al (1994Friedgen et al ( , 1996a reported total plasma clearances for 3 H-adrenaline, 3 H-noradrenaline and 3 H-dopamine of 86, 78 and 151 ml kg -1 min -1 , respectively, in normal rabbits (Friedgen et al 1994) and 67, 61 and 98 ml kg -1 min -1 , respectively, in rabbits with MAO and COMT inhibited (Friedgen et al 1996a). Comparison of these plasma clearances with the Cl u values obtained here ( Fig.…”

“…were given. Blood pressure and heart rate were continuously recorded via the right carotid artery, and the thermodilution technique was used to measure cardiac output (for details, see Friedgen et al 1994Friedgen et al , 1996a.…”

Adrenaline and Noradrenaline: Partners and Actors in the Same Play"

“…It has been shown that NET inhibitors (e.g., cocaine, imipramine, and desipramine) potentiate the effects of the neurotransmitters, while inhibitors of MAO and COMT have relatively little immediate effect (Gonçalves et al, 1989, Eisenhofer, 1994, Eisenhofer and Finberg, 1994, Friedgen et al, 1994, Blaha et al, 1996, Friedgen et al, 1996. Early studies in isolated tissues showed that the inhibition of MAO or COMT could limit the ability of neuronal and extraneuronal uptake to clear extracellular catecholamines (Furchgott andGarcia, 1968, Belfrage et al, 1977).…”

“…Early studies in isolated tissues showed that the inhibition of MAO or COMT could limit the ability of neuronal and extraneuronal uptake to clear extracellular catecholamines (Furchgott andGarcia, 1968, Belfrage et al, 1977). More recent in vivo studies however indicate that inhibition of one enzyme under normal physiological conditions has little effect on the overall catecholamine clearance and on their extracellular or circulating levels (Eisenhofer, 1994, Eisenhofer and Finberg, 1994, Friedgen et al, 1994, Blaha et al, 1996, Friedgen et al, 1996. Only when MAO and COMT are both inhibited or subjected to saturating concentrations of substrate, the clearance of catecholamines is significantly impaired (Eisenhofer, 1994, Friedgen et al, 1996.…”

“…More recent in vivo studies however indicate that inhibition of one enzyme under normal physiological conditions has little effect on the overall catecholamine clearance and on their extracellular or circulating levels (Eisenhofer, 1994, Eisenhofer and Finberg, 1994, Friedgen et al, 1994, Blaha et al, 1996, Friedgen et al, 1996. Only when MAO and COMT are both inhibited or subjected to saturating concentrations of substrate, the clearance of catecholamines is significantly impaired (Eisenhofer, 1994, Friedgen et al, 1996. To confirm the redundancy of metabolizing systems, in MAO-A-deficient humans or rats a marked decrease in deaminated catecholamine metabolites and a concomitant marked elevation of O-methylated amine metabolites occur Finberg, 1994, Lenders et al, 1996).…”